Neurodegenerative diseases (ND) are CNS disorders characterized by progressive cell death of neurons that ultimately leads to cognitive and motor deficits. These diseases effect more than 5 million people in the U.S. and by 2010, 20 million people world- wide are projected to suffer from some form of ND. Despite these large numbers, ND remains an unmet medical need, receiving relatively little attention from the pharmaceutical industry. It is clear that the discovery of disease-modifying drugs for ND will require the implementation of a new research model that is not so dependent on industry. One such model has been put into operation in the Laboratory for Drug Discovery in Neurodegeneration (LDDN). The LDDN was established in late 2001 to collaborate with the Harvard Medical School neuroscience communityto discover chemical entities that could become the starting points for development into a new generation of drugs to treat ND. During its first two years, the LDDN has worked on no less than twenty projects and launched half-a-dozen medicinal chemistry projects. The LDDN has now reached a critical stage in the development of its drug discovery model where it has become essential to expand its collaborative interactions to include laboratories from around the country and to create a NATIONAL CENTER FORDRUG DISCOVERY INNEURODEGENERATION (NCDDN). This proposal outlines the creation of this center and has as its specific aims the establishment of key elements of organizational infrastructure (e.g., steering committee, milestones, sharing of intellectual property, and publication policy) as well as a detailed research plan that will be applied to five new drug discovery projects each year for five years. The drug discovery research of this proposal is driven by close interaction between permanent staff members of the NCDDN and an investigatorthat comes from the collaborating laboratory. Together, they will extend the discoveries in basic neuroscience that the collaboration investigator (CI) brings to the NCDDN from the "home" lab and (i) develop a precise assay suitable for high-throughput screening, (ii) screen tens of thousands of drug-like molecules that comprise LDDN's growing compound library, (iii) identity and validate screening "hits", and (iv) conduct a limited program of exploratory medicinal chemistry to optimize compound potency. For successful programs, the research plan provides for additional studies that will continue beyond the CI's one year tenure in the NCDDN and include a more extensive program of medicinal chemistry-driven optimization of the lead series of compounds as well as efficacy testing of these compounds in animal models of disease. The final phase of this work, and the over-arching goals of the LDDN and NCDDN, will go beyond the support requested in this application, but will include the crafting of partnerships with industry to bring disease-modifying drugs to patients jsufferingjTom ND._ In this revised application, we have: (i) specially clarified the nature and operating principles of the Steering Committee, (ii) revised and expanded on the policies relating to the pursuit of intellectual property and the distribution -of research-derived materials, (iii) outline more clearly milestones and GO/NOGO decision points for projects, (iv) exp_anded the resoupoundces for medicinal chemistry, and,(iy), described_efficacy sjudjesjnjammal[models.andJjojw we wilLget them done.